Review

Drug-herb interactions: Mechanisms involved and clinical implications of five commonly and traditionally used herbs

Chin Eng Ong1,*, Yan Pan2

1School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, 46150 Bandar Sunway, Selangor, Malaysia; 2School of Biomedical Sciences, The University of Nottingham Malaysia Campus, Jalan Broga, 43500 Semenyih, Selangor, Malaysia

ABSTRACT Herbal remedies are commonly used by patients worldwide. Because these herbal preparations share the same metabolic and transport proteins with prescribed medicines, the potential for a drug-herb interaction is substantial and is an issue of significant concern. This review paper summarizes drug-herb interactions involving inhibition or induction of cytochrome P450 enzymes, drug transporters as well as modulation of drug pharmacodynamics. An increasing number of in vitro and animal studies, case reports and clinical trials evaluating such interactions have been reported, and implications of these studies are discussed in this review. The most commonly implicated drugs in the interaction include anticoagulants, antiplatelets, immunosuppressants, anti-neoplastics, protease inhibitors, and some antidepressants. Pharmacokinetic and/or pharmacodynamic interactions of five commonly used herbal remedies (danshen, garlic, Ginkgo biloba, ginseng, and St John’s wort) with these drugs are presented, with focus of discussion being the potentials for interaction, their mechanisms and clinical implications. There is a necessity for adequate pharmacovigilance to be carried out in minimizing unanticipated but often preventable drug-herb interactions.

Keywords cytochrome P450, drug-herb interaction, P-glycoprotein, pharmacodynamics, pharmacokinetics

INTRODUCTION identity of the chemical constituents from a natural product is unknown. As a result, both adverse drug reactions and Patients usually take several drugs for the treatment of one or poisonings associated with the use of herbal remedies have more health problems at the same time. Metabolic drug-drug increasingly been reported (Deng, 2002; Shi and Klotz, 2012). interactions occur when a drug inhibits or induces the activity It is likely that constituents in herbal preparations may module of a drug-metabolising enzyme, which catalyses the or interfere with the pharmacokinetics and pharmacodynamics metabolism of a concomitantly administered drug. Interaction of co-administered drugs, resulting in drug-herb interactions. however is not limited to drugs but includes also other supplements that patients may be taking at the same time including vitamins, minerals, food supplements and herbal COMMON MECHANISMS OF INTERACTION remedies. Herbal medicines have been used worldwide since ancient times. Archeological evidence and pollen analysis from The clinical importance of any drug interaction depends on a Neanderthal burial site in modern day Iraq indicate that the several factors, including the condition of the patient, the drugs use of medicinal plants may be dated back to 50,000 B.C. administered, the route of administration, the environment, the (Solecki and Shanidar, 1975). An estimated one third of adults therapeutic index, as well as the timing of administration of the in the United States use alternative therapies, including herbs drugs (Kremers, 2002). The possible causes of drug interactions (Kauffmanet et al., 2002; Shi and Klotz, 2012). It has also been can be summarized as follows: reported that 20% of the general population in the United  Competition for gastrointestinal absorption Kingdom used complementary or alternative medicine in the  Binding to plasma proteins course of a year (Zhou et al., 2004). There is a common belief  Binding to transport proteins among the general public that herbal preparations are “good for  Pharmacodynamic interactions at receptor level humans” as they are “all natural” (Solecki and Shanidar, 1975).  Inhibition of metabolism However, they are complex mixtures of bioactive entities that  Induction of metabolism may or may not provide therapeutic activity. Usually, the  Competition for active renal excretion The gastrointestinal absorption of drugs may be affected by *Correspondence: Chin Eng Ong concurrent use of other agents due to the large surface area of E-mail: [email protected] the tract upon which the drug can be absorbed, bind or chelate, Received February 11, 2014; Accepted August 18, 2014; Published or alter in term of gastrointestinal motility. The mechanisms by August 31, 2014 which drug interactions alter drug distribution include doi: http://dx.doi.org/10.5667/tang.2014.0008 competition for plasma protein binding and displacement from ©2014 by Association of Humanitas Medicine tissue binding sites. And this binding can increase the free This is an open access article under the CC BY-NC license. concentration (and thus the effect) of the displaced drug in (http://creativecommons.org/licenses/by-nc/3.0/)

TANG / www.e-tang.org 2014 / Volume 4 / Issue 3 / e17 1 Drug interactions with herbal remedies plasma. Pharmacologic interactions between agonists and therefore harmless, they are not free from adverse effects. A antagonists happen at specific receptor sites, resulting in the recent observational study indicates that herbal supplements are effects of drugs being blocked or changed. From the drug associated with adverse events that include all levels of severity, metabolism perspective, one notable system involved in organ systems, and age groups (Palmer et al., 2003). A relevant metabolic drug interactions is the enzyme system comprising safety concern associated with the use of herbal remedies is the the cytochrome P450 (CYP) monooxygenases. This system risk of interaction with prescription medications. This issue is may be affected by either enzyme induction or enzyme especially important with respect to drugs with narrow inhibition. For instance, drug A induces the body to produce therapeutic indices, such as warfarin or digoxin (Shi and Klotz, more of an enzyme which metabolises drug B. This reduces the 2012). In clinical practice, polypharmacy is common, in effective concentration of drug B, which may lead to loss of its addition to medicines prescribed by their physicians; patients effectiveness. On the other hand, drug C inhibits the production may be taking various over-the-counter medications, vitamins, of the enzyme metabolising drug B, thus an elevation of drug B herbs and food supplements concurrently. All ingested occurs possibly leading to an overdose. The renal excretion of substances have the potential to interact, resulting in various active drug can also be affected by concurrent drug therapy, clinical problems such as therapeutic failure, drug adverse thus altering serum drug level and pharmacologic response. effect and toxicity, and altered patient response to therapy. Herbal remedies are mixtures of more than one active ingredient. Hence, the likelihood of drug-herb interaction is theoretically higher than drug–drug interaction because COMMONLY USED HERBS IMPLICATED IN synthetic drugs usually contain single chemical entities. The DRUG INTERACTION interaction is likely to follow the same pharmacokinetic and pharmacodynamic mechanisms as seen in drug–drug Potential drug-herb interactions have been reported in a wide interactions (Izzo et al., 2002; Shi and Klotz, 2012). Drug–herb variety of laboratory, animal and human studies. Furthermore, interactions can occur when herbs and drugs are co- herbal remedies have been shown to interact clinically with administered and the herbal preparation (one or more many prescribed drugs. Table 1 lists some of the most components) modulates the metabolism of the drugs. Moreover commonly used herbs which have been reported to cause drug herbal components can also be metabolised by CYPs or other interactions. Discussion on how these herbal remedies may drug-metabolising enzymes thus further complicating the affect the pharmacokinetic and pharmacodynamic profiles of mechanism. prescribed drugs will be discussed in the ensuing sections.

Danshen CLINICAL RELEVANCE OF DRUG-HERB Danshen, the dried root and rhizome of Salvia miltiorrhiza INTERACTIONS Bunge, is a widely used medicinal plant in China and a complementary medicine in the West. Because of its properties The metabolism of a drug can be altered by another drug or in improving microcirculation, causing coronary vasodilatation, foreign chemical and such interaction can often be clinically inhibiting platelet adhesion and aggregation, suppressing the significant. Inhibition of the metabolism of a drug will lead to formation of thromboxane, and protecting against myocardial an elevation of its concentration in tissues, which might result ischemia, it is widely used either alone or in combination with in various adverse reactions, particularly for drugs with low other herbs for cardiovascular and cerebrovascular diseases therapeutic indices. For example, fluconazole, a potent including angina pectoris, thrombosis, hyperlipidaemia, acute inhibitor of an important human CYP isoform, CYP2C9, ischaemic stroke and hypertension (Cheng, 2007; Gao et al., resulted in reduction of approximately 70% of the metabolic 2012; Lam et al., 2006). Danshen is indexed in the 2010 clearance of S-warfarin, leading to organ bleeding in patients Chinese Pharmacopoeia, with more than 35 formulations and (Black et al., 1996). Inhibition of CYPs has also led to the concoctions containing Danshen water-extracts, ethanolic withdrawal of several marketed drugs during the past decades. extracts or their combination, each with descriptions and details The calcium channel blocker mibefradil (Posicor) used for the on the standards of purity, testing, dosage, precautions, storage, treatment of hypertension and chronic angina pectoris was and the strength. Danshen products may be standardized voluntarily withdrawn by Roche from the US market in 1998 according to major constituents which include tanshinones because it was a potent mechanism-based enzyme inhibitor that (dipertenequinones), salvianolic acid (a polyphenolic acid) and significantly increased the plasma concentration of other related danshensu compound, 3,-4-dihydroxyphenyllactic acid cardiovascular drugs (such as propranolol and verapamil) to (Gao et al., 2012). This herb possesses low to moderate toxic levels (Mullins et al., 1998). The non-sedating potential to interact with prescribed drugs and one important antihistamines terfenadine and astemizole were withdrawn drug group affected is the anticoagulants which include from the US market because of remarkable metabolic inhibition warfarin. by other drugs leading to life-threatening arrhythmias (Dresser Case reports and animal data indicate that danshen can et al., 2000). In addition, the effectiveness of some prodrugs increase the effects of warfarin resulting in bleeding. The may be modulated by changes in CYP activities, for instance, anticoagulant effect of warfarin was reported to be increased in CYP inhibition may result in a decrease in the formation of the two patients as a result of ingestion of danshen (Izzat et al., active species, possibly leading to therapeutic failure due to 1998; Yu et al., 1997). In both cases, patients’ international lack of efficacy of the drug. Tamoxifen, a selective estrogen normalized ratio (INR) was dramatically raised (to more than 5, receptor modulator, could significantly reduce the conversion from the target range of 2 - 3) after danshen intake. After of the prodrug losartan to its active carboxylic acid metabolite discontinuing danshen, the patients were able to be stabilized (E-3174) by inhibiting the activity of hepatic CYP2C9 in breast on warfarin with INR back to desired range in the absence of cancer patients, hence affecting the efficacy of the angiotensin danshen. Animal studies in rats demonstrate that administration II receptor antagonist (Boruban et al., 2006). of danshen aqueous extract was able to prolong prothrombin The interaction problem applies similarly to herbal time and increase the steady state levels of both isomers of remedies. Although herbs are often promoted as natural and warfarin (Chan et al., 1995; Lo et al., 1992). The mechanism of

TANG / www.e-tang.org 2014 / Volume 4 / Issue 3 / e17 2 Drug interactions with herbal remedies this interaction is uncertain but animal and in vitro studies which converts the sulfoxides to their respective thiosulfinates. suggest that danshen may impair haemostasis with its The thiosulfinates may eventually be reduced to sulfides that antiplatelet actions and therefore the action may be additive to are responsible for unfavourable breath odour after garlic the anticoagulant effect of warfarin. Available evidences consumption (Block, 1985; Singh and Singh, 2010). Garlic has suggest that interaction of danshen with drugs via modulation in general low potential for interaction, but clinical studies and of CYP activities seems unlikely and is of little clinical case reports have reported the ability of this herb to interact relevance. Limited in vitro and animal studies indicate that with some important drug groups including protease inhibitors, danshen had inductive effect on CYP1A2 activity but the effect taxane anticancers, anticoagulants and antiplatelet agents. appeared to be limited to ethyl extracts of danshen (Kuo et al., Some of these interactions may warrant close monitoring of 2006; Ueng et al., 2004), and not the aqueous extract which is drug therapy to minimize adverse event or therapeutic failure. the form more commonly consumed by patients. This effect Garlic is commonly used by HIV-infected patients to may not be clinically relevant, as clinical studies with improve health and to treat some opportunistic infections, and theophylline, the substrate probe for CYP1A2, did not find a it has the potential for interactions with anti-HIV drugs clinically relevant interaction (Qiu et al., 2008). Similarly including protease inhibitors (Borrelli et al., 2007). A clinical studies on CYP2C9 and CYP3A4 (using tolbutamide and study in healthy subjects has indicated that garlic nifedipine as probes) also indicate negligible interaction with supplementation resulted in a significant decline (as much as danshen (Kuo et al., 2006). Therefore there remains minimum 54%) in plasma concentrations of saquinavir (Piscitelli et al., risk of pharmacokinetic interaction between danshen and 2002) but the same was not observed in another study with prescribed drugs via modulation of CYP activity. ritonavir (Gallicano et al., 2003). The mechanism of interaction Considering all the available evidences, it is possible that with saquinavir is uncertain, but it is thought that garlic reduced danshen, by its platelet inhibitory effect, may increase bleeding the bioavailability of saquinavir by induction of CYP enzymes, risk in patients stabilized on warfarin and other anticoagulants. in particular, CYP3A4, as well as P-glycoprotein in the It is therefore important for patients taking anticoagulants to be intestine (Piscitelli et al., 2002). Garlic effect on other protease closely monitored and be advised to stop consuming danshen or inhibitors is unknown and therefore this interaction may not be use an alternative. Risk for interaction of danshen with CYP generalized and apply to other antiretroviral agents. However, drug substrates, on the other hand, appears to be remote as the magnitude of reduced saquinavir concentration as reported negligible pharmacokinetic interactions have been reported. in Piscitelli et al. (2002) is expected to decrease antiviral effect in some patients. As such, patients taking saquinavir should Garlic avoid chronic and high-dose garlic administration. Interaction Garlic (Allium sativum) a common food and flavouring agent of garlic with docetaxel, another CYP3A4 substrate, has also used throughout the world, is one of the earliest known been reported. Systemic clearance of docetaxel was reduced by cultivated plants and is one of the most frequently used herbal 65 - 77% in ten women with metastatic breast cancer when co- supplements. It has been generally used for the treatment of administered with garlic (Cox et al., 2006). Thus, combination hypercholesterolaemia, prevention of arteriosclerosis, and other of the anticancer with garlic may warrant patient monitoring. conditions such as cancer, because it is believed to have Because garlic has complex cardiovascular effects, including antibacterial, antiparasitic, antilipidemic, antihypertensive, anticoagulant and antiplatelet activity, its potential to interact anticancer and antioxidant activities, and to improve immune with anticoagulant or antiplatelet drugs cannot be ruled out. function. Garlic contains a large number of biologically active One case report suggested that garlic can increase INR in constituents. These include more than 30 organic sulfur patients previously stabilized on warfarin (Vaes and Chyka, compounds derived from cysteine derivatives such as S-allyl-L- 2000) and another reported decreased INR in patients receiving cysteine. Alliin (S-ally-L-cysteine sulfoxide) and related another anticoagulant fluindione (Pathak et al., 2003). These compounds are converted into thiosulfinates responsible for the observations however were not supported by a placebo- familiar odour of fresh garlic. Allicin (diallyl thiosulfinate), one controlled study which demonstrated the lack of effect on INR of the more highly studied components of garlic, is not present with concurrent garlic administration (Morris et al., 1995). The until the garlic bulb is crushed, releasing the enzyme alliinase, available data are thus not sufficient to establish the clinical Table 1. Clinical relevance of drug-herb interactions Potential for Herb Mechanism(s) Victim drug(s) interaction Danshen Low to moderate Inhibition of platelet aggregation Warfarin (Salvia miltiorrhiza) Induction of CYP3A4 and P-glycoprotein Saquinavir Garlic Modulation of CYP3A4 activity Docetaxel Low (Allium sativum) Warfarin Inherent antcoagulant and antiplatelet activity Fluindione Omeprazole Modulation of CYP enzymes Nifedipine Ginkgo biloba Moderate Warfarin Inhibition of platelet aggregation Aspirin Cilostazol Ginseng Inhibition of CYP3A4 Nifedipine (Panax ginseng, Induction of CYP2C9 or inherent antiplatelet Low to moderate Warfarin Panax quinquefolius, activity Eleutherococcus senticosus) Nepherotoxicity of the loop of Henle Loop diuretics Protease inhibitors Induction of CYP enzymes and P-glycoproteins St John’s wort Immunosuppressants High (Hypericum perforatum) Fluoxetine Additive serotonin effect Rasagilene

TANG / www.e-tang.org 2014 / Volume 4 / Issue 3 / e17 3 Drug interactions with herbal remedies importance of the interactions. platelet aggregation, clotting time and platelet count were Overall, interactions of garlic with saquinavir, docetaxel, unaltered (Aruna et al., 2006). In vitro evidence suggests that G. warfarin and fluindione have been reported. The causal biloba inhibited platelet aggregation, but the clinical relevance relationship and clinical importance of these interactions have of this effect is not established (Bone, 2008). Nonetheless, the not been well established. While further information is awaited, combination of drugs affecting blood coagulation with G. caution is advised if garlic is taken concomitantly with the biloba should generally be avoided due to the potential for above mentioned drugs or other drugs from the same serious bleeding complications which can be life-threatening. therapeutic classes. In conclusion, G. biloba has been shown to modulate some CYP isoforms and platelet aggregation. G. biloba-drug Ginkgo biloba interactions were also demonstrated in some clinical studies. The ginkgo is the oldest living tree species, geological records While potential for interaction is moderate only, caution should indicate this plant has been growing on earth for 150 to 200 still be exercised with combination of G. biloba and the above million years (Defeudis and Drieu, 2000). Chinese monks are mentioned drugs. credited with keeping the tree in existence, as a sacred herb. It was first brought to Europe in the 1700's and it is now among Ginseng the most popular herbal remedy worldwide. Ginkgo biloba is For centuries ginseng has been used as a traditional herbal used for the treatment of cerebral insufficiency or peripheral medicine in many Asian countries. Today ginseng products are vascular disease, and is frequently taken for enhancement of consumed worldwide and rank among the most commonly used memory function (Weinmann et al., 2010). The flavonol herbal products. Several species of ginseng are available on the glycosides (including aglycone and glycosides of kaempferol, market including Panax ginseng (Asian ginseng), Panax quercetin, and isorhamnetin) and terpene trilactones (such as quinquefolius (American ginseng) and Eleutherococcus bilobalide, ginkgolide A, ginkgolide B, ginkgolide C, and senticosus (Siberian ginseng). Ginseng has diverse ginkgolide J) are the major constituents of G. biloba (van Beek pharmacological activities, including effects on the central and Montoro, 2009). Some of these constituents (ginkgolide, nervous system, antineoplastic and immunomodulatory effects. bilobalides and others) have antiplatelet activity and are Ginseng products are advocated for many conditions, including platelet-activating factor (PAF) receptor antagonists (Bone, maintenance of general health, physical and mental well-being, 2008), hence the main use of this herb in neurological disorders treatment of fatigue, weakness and mild depression, improving and circulation problems. The herb has moderate potential for immune function, and for conferring antioxidant effect (Attele drug interactions where interaction with prescribed drugs et al., 1999). Its major active components are ginsenosides, a including proton pump inhibitors, calcium channel blockers group of steroidal saponins, which exhibit most of the and drugs affecting blood coagulation (anticoagulants and pharmacological actions above (Qi et al., 2011). The herb antiplatelet agents) have been reported (Shi and Klotz, 2012). possesses low to moderate potential for drug interactions. The effect of G. biloba on various CYP isoforms has been Major groups of drugs reported to be affected include calcium widely investigated in clinical studies. In most studies, G. channel blockers, anticoagulants and loop diuretics. biloba had no significant effect on CYP1A2, CYP2D6, Interaction with calcium channel blockers appears to CYP2E1, CYP2C9 or CYP2B6 (Greenblatt et al., 2006; Gurley involve modulation of CYP activity. In vitro effect of ginseng et al., 2005; Lei et al., 2009; Markowitz et al., 2003). One of on CYP isoforms have been investigated (Chang et al., 2002; the studies examined the effect of the herb on the Foster et al., 2002; He et al., 2006; Yu et al., 2005). Most pharmacokinetics of omeprazole in Chinese subjects previously studies however showed only weak to moderate degree of genotyped for CYP2C19. Twelve days of treatment with G. inhibition or induction, and the effects are not likely to be biloba induced hydroxylation of omeprazole in a CYP2C19 clinically significant. Clinical trials or case reports on ginseng- genotype-dependent manner. Concurrently, renal clearance of drug interactions are limited. Ginseng inhibition of CYP3A4 5-hydroxyomeprazole was reduced (Yin et al., 2004). This was statistically significant in a clinical trial (Smith et al., study has demonstrated the ability of G. biloba in inducing 2001). The magnitude of the effect however was rather modest CYP2C19 activity and the inductive effect may probably apply with increase of only 29% in plasma concentration of to other major CYP2C19 substrates in addition to omeprazole. nifedipine, the CYP3A4 substrate probe. The increase of this Therefore caution should be exercised when co-administering magnitude would be expected to produce only small changes in CYP2C19 substrates (in particular omeprazole) and G. biloba. patient response. Potential interactions between ginseng and The effect of G. biloba on another isoform CYP3A4 is less warfarin have been documented in case reports whereby the consistent. In one clinical trial, G. biloba decreased the area warfarin anticoagulant effect (measured by INR or warfarin under the plasma concentration-time curve (AUC) and plasma concentration) was found reduced (Janetzky et al., 1997; maximum concentration (Cmax) of midazolam by 34% and Rosado, 2003). Although mechanism of this interaction is not 31%, respectively, suggesting that G. biloba could induce clear, modulation of CYP activity might be one of the possible CYP3A (Robertson et al., 2008). Oral ingestion of the herb did reasons. Induction of CYP2C9, the most important warfarin- not significantly affect the pharmacokinetics of nifedipine, metabolizing isoform, has been proposed as the mechanism another CYP3A4 substrate. However, in two subjects, the (Gurley et al., 2002) although further studies are needed to Cmax of nifedipine was approximately doubled. In addition, verify it. Another mechanism could be the antiplatelet activity both subjects had more severe and longer-lasting headaches, of ginseng. In vitro experiments have found that the herb dizziness or hot flushes, and a trend towards higher heart rates contains antiplatelet components that inhibit platelet when G. biloba was co-administrated (Yoshioka et al., 2004). In aggregation and thromboxane formation (Kuo et al., 1990). the case of anticoagulants and antiplatelets, isolated cases of This activity however was not demonstrated in a study with bleeding have been reported following the use of G. biloba with healthy subjects (Beckert et al., 2007). In a case report of warfarin and aspirin (Matthews, 1998; Rossenblatt and Mindel, concurrent intake of furosemide and ginseng in a patient, 1997). In another study involving another antiplatelet, ginseng appeared to inhibit diuretic response to the loop cilostazol, prolonged bleeding time was observed when G. diuretic where temporal relationship between ginseng ingestion biloba was added to patients taking cilostazol even though and resistance to furosemide was observed (Becker et al., 1996).

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It was possible that ginseng may have induced nephrotoxicity The concurrent use of these drugs with the herb should be involving the loop of Henle resulting in refractoriness to avoided because of increased risk of the neurologic adverse furosemide. The clinical importance of this effect is effect, and where combination is unavoidable, proper lapse nevertheless not well established and more controlled studies time should be instituted between dosing of the drugs and the are needed to confirm it. herb. In summary, the available clinical evidences suggest that Based on the discussion above, it is apparent that a large the potential for ginseng-drug interactions is low to moderate number of studies have indicated that St John’s wort can cause only. Caution is however advised when patients are taking both pharmacokinetic and pharmacodynamic interactions. The anticoagulants and loop diuretics together with ginseng, and potential for drug-herb interactions is high; therefore, patients patient response to drug therapy should be monitored and taking prescribed drugs should be discouraged from taking assessed. herbal products containing St John's wort.

St. John’s wort St John’s wort (Hypericum perforatum), one of the oldest and CONCLUSION best investigated herbal remedies, is the most commonly used herbal antidepressant for treatment of mild to moderate Drug-herb interactions listed in Table 1 have provided evidence depression (Solomon et al., 2011). H. perforatum is a yellow- that co-administration of prescribed medicines and herbal flowering, perennial herb indigenous to Europe that has been products could lead to serious adverse reactions caused by introduced to many temperate areas of the world and grows interactions. While potential for interaction remains low for wild in many meadows. The common name comes from its many herbs, there are some which have demonstrated moderate traditional flowering and harvesting on 24 June, the birthday of to high potential. There is therefore a necessity for adequate John the Baptist (St John’s Day). Many clinical trials have pharmacovigilance to be carried out in minimizing demonstrated efficacy of the herb to be superior to placebo and unanticipated but often preventable drug-herb interactions. comparable to standard antidepressants but with fewer side During the course of drug treatment, patients should be effects (Linde et al., 2008). When used as a single agent, a encouraged to tell their health care providers which herbal favourable risk/benefit ratio has made St John’s wort one of the remedies they are taking, and the health care providers should most readily consumed dietary supplements in the world. Its be sufficiently informed to provide useful advice for their popularity however has also contributed to its distinction as patients. Availability and application of this information is being one of the most problematic dietary supplements with critical, particularly in elderly patients who are at higher risk of regard to drug-herb interactions. The herb does indeed possess adverse interactions, especially as polypharmacy is often high potential for drug interactions, and by far, it is one of the practised in this population (Klotz, 2009). Thus, increased most extensively studied herbs in relation to drug-herb knowledge of drug-herb interactions would enable health care interactions (Vlachojannis et al., 2011). Combination of the providers and patients to be alert to the potential of interactions, herb with protease inhibitors (including indinavir, ritonavir, and to improve the treatment outcomes. saquinavir, darunavir and atazanavir), oral contraceptives, immunosuppressants (including cyclosporine and tacrolimus), and psychoactive drugs affecting serotonergic pathway ACKNOWLEDGEMENTS (including rasagiline) should be avoided. If combination is unavoidable, close monitoring of drug response and dose None. adjustment should be instituted in patient management. Hyperforin, an active constituent of St John’s wort, appears to be an inducer of many CYP isoforms and it may also induce CONFLICT OF INTEREST P-glycoprotein (Butterweck et al., 2007). Both mechanisms lead to reduced plasma concentrations of victim drugs. Clinical The authors declare that there is no conflict of interest. studies investigating interaction between protease inhibitors and the herb showed that administration of St John’s wort resulted in decrease of AUC and Cmax of the antiretroviral REFERENCES agents (de Maatet al., 2001; Hafner et al., 2010; Piscitelli et al.,

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TANG / www.e-tang.org 2014 / Volume 4 / Issue 3 / e17 7 Drug interactions with herbal remedies of Ginkgo biloba leaves, extracts, and phytopharmaceuticals. J dietary supplements and medicines: IV. Effects of Ginkgo Chromatogr A. 2009;1216:2002-2032. biloba leaf extract on the pharmacokinetics and pharmacodynamics of nifedipine in healthy volunteers. Biol Vlachojannis J, Cameron M, Chrubasik S. Drug interactions Pharm Bull. 2004;27:2006-2009. with St John’s wort products. Pharmacol Res. 2011;63:254-256. Yu CM, Chan JC, Sanderson JE. Chinese herbs and warfarin Weinmann S, Roll S, Schwarzbach C, Vauth C, Willich SN. potentiation by 'danshen'. J Intern Med. 1997;241:337-339. Effects of Ginkgo biloba in dementia: systematic review and meta-analysis. BMC Geriatr. 2010;10:14. Yu CT, Chen J, Teng XW, Tong V, Chang TK. Lack of evidence for induction of CYP2B1, CYP3A23, and CYP1A2 gene Yin OQ, Tomlinson B, Waye MM, Chow AH, Chow MS. expression by Panax ginseng and Panax quinquefolius extracts Pharmacogenetics and herb-drug interactions: experience with in adult rats and primary cultures of rat hepatocytes. Drug Ginkgo biloba and omeprazole. Pharmacogenetics. Metab Dispos. 2005;33:19-22. 2004;14:841-850. Zhou S, Koh HL, Gao Y, Gong ZY, Lee EJ. Herbal Yoshioka M, Ohnishi N, Koishi T, Obata Y, Nakagawa M, bioactivation: the good, the bad and the ugly. Life Sci. Matsumoto T, Tagagi K, Takara K, Ohkuni T, Yokoyama T, 2004;74:935-968. Kuroda K. Studies on interactions between functional foods or

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